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Integrated Analyses of Safety Data needed! Marie Louise Valentin, MD Director of Corporate Drug Safety Agenda Integrated Safety Outputs (ISOs): • • • • Regulatory purposes Signal Detection Presentations: Consistency and Clarity Risk Management Plans (RMPs) MedDRA: – Standardised MedDRA Queries (SMQs) The Issue • Applications and regulatory documents only summarize the safety database • Statisticians today only analyse safety data across trials, when: – Potential problems arise or – The application is for a product from a class with a known safety concern Future • Health Authorities require more regular integrated safety analyses Purpose of Integrated Safety Outputs Many regulatory documents require reporting of safety information: 1. 2. 3. 4. 5. 6. IND Annual Report (FDA) Annual Safety Report (EMEA) Investigator’s Brochure Risk Management Plans DMC Data Packages Investigational Medical Product Dossier (Risk/Benefit) 7. Integrated Safety Summary – CTD Integrated Safety Outputs • Regular Integrated Safety Reviews – To be produced at least annually – Pool or combine data across studies – Present data from several studies in a single • display Gain – Provide coordinated and routine review of integrated safety data – Assist with the compilation of regulatory documents reporting safety information/ DMC data/RMP updates etc. Considerations for Pooling or Combining Data Main goal • More precise estimates by increasing the safety database In general, ISO produced by indication or formulation: • Backgound AE may differ according to patient population • Severity of disease may lead to different assessments of risk/benefit • The dose, formulation and duration of treatment may differ Across indication/formulations beneficial: • Investigational product developed for related indications • Characterize a particular AE of interest • Investigate class effects The AE profile may be related to… • • • • • • • • • • Route of administration Dose Number of dosages Duration of exposure Time since dosing Indication Stage of disease treated Concomitant medication/disease Effect on target cell/organ e.g. B-lymphocytes Demography Signal Detection • No systematic tools or methods in use within the industry • Need to account for all safety data, not just AE records • Monitor laboratory results for an increase in abnormalities • Currently done manually, more efficient and consistent with standard checks pre-defined and applied to all studies • Focus on three main areas (the most common reasons to terminate projects): – Hepatotoxicity – Nephrotoxicity – Haematotoxicity (Liver) (Kidney) (Blood) Operational Issues • Maintenance of treatment blind – Should not be an impediment to a full ongoing • • • review of safety data? Who should have access to data and results? Should DMCs review un-blinded data? False signals – Problem or proactive pharmacovigilance? • A policy for ’Integrated Safety Outputs’ should be prepared Risk Management Plans (RMP) The overall purpose of a Risk Management Plan is to describe efforts in: – Identifying – Estimating – Evaluating – Communicating – Minimising risks that may be associated with the product. Risk Management Plans EMEA: • Guideline on Risk Management Systems for Medicinal Products for human use – Effective date 20 November 2005 FDA: • Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiological Assessment • Pre-marketing Guidance • Pharmacovigilance Guidance (postmarketing) • March 2005 Risk Management Plans • Be product-specific • Balance assessment of risks and benefits • Monitor difference between clinical trials and • • • ”real life” Identify what is known at licensing Identify what is not known Clarify epidemiology of disease and known adverse effects What we know and don’t know Know: • Population treated • Time treated • Time to adverse events • Identify specific risk groups • Stratify analysis by dose, duration etc Don’t know: • Interactions • Populations not studied: Children, elderly, pregnancy • Relevance of class effects • Long term effects When do we need a Risk Management Plan? When initiating trials in • New active substances • New indications – incl extension to a • different population New routes/formulations Standardised MedDRA Queries • After the initial effort to implement and use MedDRA, the industry now focuses on data analysis with MedDRA – How to produce data summaries based on a more granular terminology • Standardised MedDRA Queries (SMQs): – Groupings of MedDRA terms that are related to a – defined medical condition Include terms related to signs, symptoms, diagnoses, syndromes, physical findings, laboratory test data Standardised MedDRA Queries • Developed in a collaboration with CIOMS, industry and regulators (Council for International Organizations of Medical Sciences, WHO and UNESCO in 1949 ) • Tested in industry and regulatory databases • Focus on significant safety issues • Currently, 16 in production and 70 in development SMQ’s in Production • Rhabdomyolysis/myopathy • Torsade de pointes/QT • • • • • • prologation Acute renal failure Hepatic disorders Haemolytic disorders Severe cutaneous adverse reactions Anaphylactic reactions Acute pancreatitis • • • • • Agranulocytosis Angioedema Asthma/bronchospasm Dyslipidaemia Haematopoietic cytopenias • Lack of efficacy/effect • Lactic acidosis • Peripheral neuropathy SMQs in 2nd phase of development • Adverse pregnancy • • • • outcome/reproductive toxicity Anticholinergic syndrome Cardiac arrhythmias Cerebrovascular disorders Convulsions • Dementia • Embolic and • • • thrombotic events Pseudomembranous colitis Retroperitoneal fibrosis Shock Standardised MedDRA Queries Available in MedDRA version 9.0 Questions